Bicyclic radical reaction

The peroxy radical formed in (Reaction 2b) is expected to cyclicize to form a corresponding bicyclic radical (Reaction 4) or react with nitric oxide via an abstraction mechanism to form the corresponding aromatic oxy radicals (Reaction 5a) ... 

Finally, a rather early (but from a mechanistic viewpoint a very interesting) sequence of radical reactions has been described by Pattenden and coworkers, in which an acetylenic oxime ether 3-312 was converted into the bicyclic oxime 3-319 in 70% yield (Scheme 3.78) [126]. Hydrolysis of 3-319 led to the bicyclic enone 3-320, which in fact can also more easily be synthesized by a Robinson annulation. 

Optically active iV-unprotected-2-pyrrolidinones 194 were obtained from selenocarboxylate or allylamine via radical cyclization and subsequent one-step cleavage of the C-O and C-N bond of the inseparable mixture of the two bicyclic oxyoxazolidinones 192 and 193 with -Bu4NF. The initial radical reaction is highly stereoselective. Products were obtained with ee up to 90%. The mandelic acid 195, which served as the chiral auxiliary in this method, was recovered with no loss of optical activity (Equation 33) <2003T6291>. 

Addition of halocarbons to alkenes in the presence of transition metals is a well-known radical reaction. Weinreb etal. have now reported an intramolecular version leading to cyclic esters or bicyclic lactones. Typical substrates are the a,a-dichloro ester 1 or the a,a-dichloro acid 2, readily available by reaction of ethyl lithiodi-chloroacetate with 5-bromo-l-pentene. When 1 is heated in benzene at 160° with a metal catalyst, mixtures of epimeric ot,w-dichloro esters 3 and 4 are obtained. The ratio and yields of 3 and 4 are dependent on the catalyst and concentration of 1, but 3 and 4 are the major products formed in the presence of Ru(II) and Fe(II) catalysts. In contrast cyclization of 2 under the same conditions gives the bicyclic y-lactone 5 in high yield. 

Another group of bicyclic aliphatic phosphines has been introduced by Sasol [15], Their ligands are based on addition of PH3 to limonene (the R-enantiomer). A mixture of two diastereomeric compounds is obtained due to the two configurations of the methyl group at the C-4 position (Figure 7.9). The Lim-H compounds obtained can be functionalised at the phosphorus atom with the usual radical reactions with alkenes or substitution reactions of their conjugate bases formed after treatment with BuLi with electrophiles. 

The reaction has also been extended to the analogous vinyl bromides [30]. Indeed, the alkenyl bromide 77 under normal reduction conditions gave the bicyclic compound 78 in good yield by an Sni reaction given by the vinyl radical (Reaction 6.17). Under these conditions, the reduction products could not be observed which suggests a very fast unimolecular reaction. 

Our approach was to use the unsaturated bromodeoxylactones in an intramolecular radical reaction, since these compounds possess both the radical precursor and the radical trap within the same molecule. Thus, reacting the unsaturated bromodeoxyheptonolactone 20 (Scheme 14) with tributyltin hydride and a radical initiator, the bicyclic lactone 65 a was obtained in a quantitative yield within 1 h. The stereocontrol in the reaction was determined by the structure of the product, since the compound obtained has two fused cyclopentane rings which can only be cis anellated. The radical A, which is the intermediate, was trapped by the tin hydride. The stereochemistry of the newly formed chiral center is determined by the configuration at C-4 in the educt 20 [45]. 

Bicyclic eight-membered ring phosphorus compounds are usually obtained by the free radical reactions of the corresponding alkenes with phosphines. In most cases, these reactions require the presence of such free radical initiators as azobis(isobutyronitrile) (AIBN) or azobis(isovaleronitrile) (VAZO). 

It was thus of interest to determine whether a transannular addition could occur for the cyclo-octenyl radical. The cyclo-octenyl radical has been prepared from its parent halohydrocarbon in several matrices in the rotating cryostat. At 77°K the radical was stabilized in all of the matrices but when the samples were warmed reaction took place. The e.s.r. spectra showed that the main reaction in matrices of water, benzene or camphane was hydrogen abstraction adjacent to the double bond to give a cyclic allyl radical (9) rather than the bicyclic radical. However, in a matrix of bicyclopentadiene dimer cyclization occurs to give the bicyclic radical and in a matrix of adamantane both allylic and bicyclic radicals were formed. 

The regioselectivity in diene addition reactions can also be influenced by ring strain effects in cyclization reactions. The regioselectivity is highly predictable in those cases, in which addition to the preferred diene center forms the preferred ring size. Thus, the cyclization of radical 15 proceeds readily to form the ct s-disubstituted cyclopentyhnethyl radical 16 with high selectivity. Similarly, cyclization of 17 affords exclusively bicyclic radical 18, in which the additional cyclopentane ring has been formed by addition to the terminal position of the butadiene subunit. This preference for 5-exo cyclizations onto dienes is not even dismpted by substiments at the C1 or C4 positions of the diene system, as seen for radical 19, which cyclizes to 20 (equation lO). This is in contrast to alkyl radical cyclizations to alkenes, in which major amounts of 6-endo cyclization is observed for 5-substituted systems. ... 

Radical reactions with organotin hydrides have been valuable for dehalogenation of organic halides. Bu3SnH/AIBN dehalogenation of a bicyclic carbamate furnished the ring-contracted product by carbamate rearrangement (Scheme 12.126) [229]. 

Radical cyclization reactions have proven to be a very efficient approach for polycyclic natural product synthesis. In many cases, the last step involves a reduction of a cyclic radical with formation of a new stereogenic center. Very good stereochemical control has been achieved with such polycyclic radicals. For example, Beckwith has reported a highly stereoselective formation of a quinolizidine ring (Scheme 19, Eq. 19.1) [41b]. This process is the key reaction in a four-step synthesis of epilupinine and the stereochemical outcome results from a stereoselective axial reduction by tin hydride of a bicyclic radical. In a related process, Tsai has prepared silylated hydroxyquinolizidine by radical cyclization to an acylsilane followed by a radical-Brook rearrangement (Scheme 19, Eq. 19.2) [42]. 

Numerous research groups have shown that chiral auxiliaries can be used in free-radical reactions for the generation of new stereogenic centers [34], Sibi and Yamamoto have used oxazolidinone chiral auxiliaries in the presence of bidentate Lewis acid to create bicyclic intermediates and control the outcome of reactions (Scheme 11). 

The development of tandem free-radical reactions offers synthetic chemists the opportunity to combine the one-carbon ring expansion reaction with other radical transformations such as cyclization [8a] and addition [8b] in the construction of ring-expanded bicyclics (Scheme 4). 

Only a few examples of tetrahydropyran syntheses from 6-exo-tng cyclizations have been reported. Photolysis of alkyl nitrate 30 and Bu3SnH affords bicyclic tetrahydropyran 31 in 68% yield (Scheme 8) [56]. Furthermore, tributylstannane-mediated O-radical reaction starting from epoxymethylene bromide 32 leads to... 

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